Method for producing, via organometallic compounds, organic intermediate products

ABSTRACT

A method for preparing aryllithium compounds of the formulae (IV) and (VI) includes reacting halogen compounds (I) with lithium metal to obtain a lithium compound of formula (II) and reacting the lithium compound of formula (II) with aromatic compounds of the formulae (III) and/or (V) to form lithium aromatics (IV) and (VI).

This Application is a 311 of PCT/EP02/11042 filed on Oct. 2, 2002.

The invention relates to a process for preparing organic compounds byproducing aryllithium compounds and reacting them with suitableelectrophiles, in which a lithium compound is firstly generated byreacting halogen compounds with lithium metal and is subsequentlyreacted with aromatic compounds to deprotonate them and form the desiredlithium aromatic which may finally be reacted, if desired, with anappropriate electrophile (equation I),

Step 1: Production of the Base

Step 2: Deprotonation of the Substrate

(Equation I)

The upswing in organometallic chemistry, particularly that of theelement lithium, in the preparation of compounds for the pharmaceuticaland agro-chemical industries and also for numerous further applicationshas proceeded almost exponentially in recent years if the number ofapplications or the amount of products produced in this way is plottedagainst a time axis. Reasons for this are essentially the ever morecomplex structures of the fine chemicals required for thepharmaceuticals and agrochemicals sectors and also the virtuallyunlimited synthesis potential of organolithium compounds for the buildupof complex organic structures.

Virtually any organolithium compound can be easily produced by means ofthe modern arsenal of organometallic chemistry and can be reacted withvirtually any electrophile to form the desired product. Mostorganolithium compounds are generated in one of the following ways:

-   (1) The most important route without doubt is halogen-metal exchange    in which usually bromoaromatics are reacted with n-butyllithium at    low temperatures.-   (2) Very many organometallic Li compounds can likewise be prepared    by reacting bromoaromatics with lithium metal.-   (3) Also very important is the deprotonation of organic compounds    with lithium alkyls (e.g. BuLi) or lithium amides (e.g. LDA or    LiNSi).

It follows from this that the use of commercially available alkyllithiumcompounds is required for the major part of this chemistry, with n-BuLiusually being used here. The synthesis of n-BuLi and related lithiumaliphatics is technically complicated and requires a great deal ofknow-how, so that n-butyllithium, s-butyllithium, tert-butyllithium andsimilar molecules are available only at very high prices, judged byindustrial standards. This is the most important but by far not the onlydisadvantage of this otherwise very advantageous and widely usablereagent.

Owing to the extreme sensitivity and, in concentrated solutions,pyrophoric nature of such lithium aliphatics, very elaborate logisticsystems for transport, introduction into the metering stock vessel andmetering have to be built up, requiring a high capital investment inplant, for the quantities wanted in industrial production (annualproduction quantities of from 5 to 500 metric tons).

Furthermore, the reactions of n-, s- and tert-butyllithium form eitherbutanes (deprotonations), butyl halides (halogen-metal exchange, 1equivalent of BuLi) or butene and butane (halogen-metal exchange) whichare gaseous at room temperature and are given off in the hydrolyticwork-ups of the reaction mixtures which are required. This results in anadditional requirement for complicated offgas purification facilities orappropriate incineration facilities in order to meet strict legalpollution regulations. As a way around this problem, specialistcompanies offer alternatives such as n-hexyllithium, but although thesedo not result in formation of butanes, they are significantly moreexpensive than butyllithium.

A further disadvantage is the formation of complex solvent mixturesafter the work-up. Owing to the high reactivity of alkyllithiumcompounds toward ethers which are virtually always solvents for thesubsequent reactions, alkyllithium compounds can usually not be marketedin these solvents. Although the manufacturers offer a broad range ofalkyllithium compounds of a wide variety of concentrations in a widevariety of hydrocarbons, halogen-metal exchange reactions, for example,do not proceed in pure hydrocarbons, so that one is forced to work inmixtures of ethers and hydrocarbons. As a result, water-containingmixtures of ethers and hydrocarbons are obtained after hydrolysis, andthe separation of these is complicated and in many cases cannot becarried out economically at all. However, recycling of the solvents usedis an absolute requirement for large-scale industrial production.

For the reasons mentioned, it would be very desirable to have a processin which the alkyllithium compound to be used for the deprotonation isproduced from the cheap raw materials haloalkane and lithium metal in anether and is simultaneously or subsequently reacted with the substrateto be deprotonated, since this procedure would enable all theabove-mentioned disadvantages of the “classical” production of lithiumaromatics to be circumvented.

The present invention achieves all these objects and provides a processfor preparing aryllithium compounds of the formulae (IV) and (VI) andalso, if desired, reacting these compounds further with suitableelectrophiles, in which a lithium compound (II) is firstly generated byreacting halogen compounds (I) with lithium metal and this is reactedwith aromatic compounds of the formulae (III) and/or (V) withdeprotonation and formation of the desired lithium aromatics (IV) and(VI) (equation I).

Step 1: Production of the Base

Step 2: Deprotonation of the substrate

(Equation I)where R is methyl, a primary, secondary or tertiary alkyl radical havingfrom 2 to 12 carbon atoms, alkyl substituted by a radical from the groupconsisting of {phenyl, substituted phenyl, aryl, heteroaryl, alkoxy,dialkylamino, alkylthio} or substituted or unsubstituted cycloalkylhaving from 3 to 8 carbon atoms,

Hal=fluorine, chlorine, bromine or iodine,

X₁₋₄ are, independently of one another, each carbon or the moietyX₁₋₄R₁₋₄ can be nitrogen or two adjacent radicals X₁₋₄R₁₋₄ can togetherbe O (furans), S (thiophenes), NH or NR′, where R′ is C₁–C₅-alkyl,SO₂-phenyl, SO₂-p-tolyl or benzoyl.

Preferred compounds of the formula (III) which can be reacted by theprocess of the invention are, for example, benzenes, pyridines,pyridazines, pyrimidines, pyrazines, furans, thiophenes, N-substitutedpyrroles, benzofurans, indoles or naphthalenes, to name only a few.

The radicals R₁₋₄ and the radical Z are substituents from the groupconsisting of {hydrogen, methyl, primary, secondary or tertiary, cyclicor acyclic alkyl radicals having from 2 to 12 carbon atoms, substitutedcyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino,arylamino, diarylamino, phenyl, substituted phenyl, alkylthio,diarylphosphino, dialkylphosphino, dialkylaminocarbonyl ordiarylaminocarbonyl, monoalkylaminocarbonyl or monoarylaminocarbonyl, C₂³¹ , hydroxyalkyl, alkoxyalkyl, fluorine and chlorine, CN andheteroaryl}, where in each case two adjacent radicals R₁₋₄ can togethercorrespond to an aromatic or aliphatic ring.

The organolithium compounds prepared in this way can be reacted with anyelectrophilic compounds by-methods of the prior art. For example, C,Ccouplings can be carried out by reaction with carbon electrophiles,boronic acids can be prepared by reaction with boron compounds, and anefficient route to organosilanes is opened up by reaction withhalosilanes or alkoxysilanes.

As haloaliphatics, it is possible to use all available or preparablefluoroaliphatics, chloroaliphatics, bromoaliphatics or iodoaliphatics,since lithium metal reacts easily and in virtually all cases inquantitative yields with all haloaliphatics in ether solvents.Preference is given to using chloroaliphatics or bromoaliphatics, sinceiodine compounds are often expensive and fluorine compounds lead to theformation of LiF which in later aqueous work-ups can form HF and lead tomaterials problems. However, such halides can also be usedadvantageously in specific cases.

In the process of the invention, preference is given to using alkylhalides which after the deprotonation can be converted into liquidalkanes.

Particular preference is given to using chlorocyclohexane orbromocyclohexane, benzyl chloride, tert-butyl chloride, chlorohexanes orchloroheptanes.

The reaction is carried out in a suitable organic solvent, withpreference being given to ether solvents, for example tetrahydrofuran,dioxane, diethyl ether, di-n-butyl ether, diisopropyl ether or anisole.Preference is given to using THF.

Owing to the high reactivity of alkyllithium and aryllithium compounds,in particular toward, inter alia, the ethers used as solvents, thepreferred reaction temperatures are in the range from −100 to +25° C.,particularly preferably from −80 to −25° C.

A further advantage of the process of the invention is that it can becarried out at quite high concentrations of organolithium compounds.Preference is given to concentrations of the aliphatic or aromaticintermediates of the formula (II) of from 5 to 30% by weight, inparticular from 12 to 25% by weight.

In the preferred embodiment, haloalkane and aromatic substrate are addedsimultaneously or as a mixture to lithium metal in ether. In thisone-pot process (simultaneous addition of (I), (III) and/or (IV) tolithium in ether), the lithium aliphatic is formed first and this thenimmediately deprotonates the aromatic. In particular cases, especiallywhen the aromatic can undergo secondary reactions with metallic lithium,it is possible firstly to produce the alkyllithium compound in ether byreaction of the haloaliphatic and lithium and only then introduce thearomatic substrate.

We have surprisingly found that in the preferred embodiment as a one-potreaction, significantly higher yields are observed in virtually allcases compared to when RLi is generated first and the aromatic substrateis added only subsequently.

In the present process, the lithium can be used as dispersion, powder,turnings, sand, granules, lumps, bars or in another form, with the sizeof the lithium particles not being relevant to quality but merelyinfluencing the reaction times. For this reason, relatively smallparticle sizes are preferred, for example granules, powders ordispersions. The amount of lithium added per mole of halogen to bereacted is from 1.95 to 2.5 mol, preferably from 1.98 to 2.15 mol.

In all cases, significant increases in the reaction rate can be observedwhen organic redox systems, for example biphenyl,4,4-di-tert-butylbiphenyl or anthracene, are added in the reaction ofthe Li metal in the first stage. The addition of such systems has beenfound to be advantageous especially when the lithiation times are >12hours without this catalysis.

Aromatics which can be used for the deprotonation are firstly allcompounds which are sufficiently acidic to be able to be deprotonatedunder the conditions according to the invention. Here, mention mayfirstly be made of all aromatics having ortho-directing substituents Z,i.e. especially aromatics bearing alkoxy, F, Cl, substituted amino, CN,heteroaryl, aminoalkyl, hydroxyalkyl or similar radicals. The mode ofaction of such radicals is based on the fact that these substituentsmake coordination of the lithium ion of the aliphatic base possible, asa result of which the counterion R⁻can then very easily deprotonate inthe ortho position.

Furthermore, all heterocycles which are strongly acidic as the result ofthe combination of a plurality of effects, for example furan, may bementioned here. The protons in this case are sufficiently acidic due to,inter alia, the inductive effect of the oxygen and due to the sp²hybridization and the angular stress on the α-carbon for deprotonationto be made possible. A similar situation applies in the case of otherheterocycles.

In the other cases in which the aromatic protons to be replaced are notsufficiently acidic, the deprotonation can nevertheless be made possibleby adding auxiliaries known to those skilled in the art for suchproblems. One auxiliary which has been found to be particularly usefulfor this purpose is potassium tert-butoxide which is added to thereaction mixture in amounts of from 0.05 to 1.2 equivalents during thelithiation of the haloaliphatic. In this way, even benzene, which has alow acidity, can be successfully lithiated (in some cases, such aprocedure forms, partially or even entirely, the potassium aromatic, butsince this has no effects on the nature of the reaction products formed,this aspect can be disregarded here).

The lithium aromatics generated according to the invention can bereacted with electrophilic compounds by the methods with which thoseskilled in the art are familiar, with carbon, boron and siliconelectrophiles being of particular interest with a view to theintermediates required for the pharmaceutical and agrochemicalindustries.

The reaction with the electrophile can either be carried out afterproduction of the lithiated compound (IV) and/or (VI) or, as describedabove, in a one-pot process by simultaneous addition to the reactionmixture.

The carbon electrophiles come, in particular, from one of the followingcategories (the products are in each case indicated in brackets):

-   aryl or alkyl cyanates (benzonitriles)-   oxirane, substituted oxiranes (ArCH₂CH₂OH, ArCR₂CR₂OH) where R═R¹-   (identical or different)-   azomethines (ArCR¹ ₂—NR′H)-   nitroenolates (oximes)-   immonium salts (aromatic amines)-   haloaromatic, aryl triflates, other arylsulfonates (biaryls)-   carbon dioxide (ArCOOH)-   carbon monoxide (Ar—CO—CO—Ar)-   aldehydes, ketones (ArCHR¹—OH, ArCR¹ ₂—OH)-   α,β-unsaturated aldehydes/ketones (ArCH(OH)-vinyl, CR¹ (OH)-vinyl)    ketenes (ArC(═O)CH₃ in the case of ketene, ArC(═O)—R¹ in the case of    substituted ketenes)-   alkali metal and alkaline earth metal salts of carboxylic acids    (ArCHO in the case of formates, ArCOCH₃ in the case of acetates,    ArR¹CO in the case of R¹COOMet)-   aliphatic nitriles (ArCOCH₃ in the case of acetonitrile, ArR¹CO in    the case of R¹CN)-   aromatic nitriles (ArCOAr′)-   amides (ArCHO in the case of HCONR₂, ArC(═O)R in the case of    RCONR′₂)-   esters (Ar₂C(OH)R¹) or-   alkylating agents (Ar-alkyl).

As boron electrophiles, use is made of compounds of the formula BW₃,where the radicals W are, independently of one another, identical ordifferent and are each C₁–C₆-alkoxy, fluorine, chlorine, bromine,iodine, N(C₁–C₆-alkyl)₂ or S(C₁–C₅-alkyl), preferably trialkoxyboranes,BF₃*OR₂, BF₃*THF, BCl₃ or BBr₃, particularly preferablytrialkoxyboranes.

As silicon electrophiles, use is made of compounds of the formula SiW₄,where the radicals W are, independently of one another, identical ordifferent and are each C₁–C₆-alkoxy, fluorine, chlorine, bromine,iodine, N(C₁–C₆-alkyl)₂ or S(C₁–C₅-alkyl), preferablytetraalkoxysilanes, tetrachlorosilanes or substituted alkylhalosilanesor arylhalosilanes or substituted alkylalkoxysilanes orarylalkoxysilanes.

The process of the invention opens up a very economical method ofbringing about the transformation of aromatic hydrogen into any radicalsin a very economical way.

The work-ups are generally carried out in an aqueous medium, with eitherwater or aqueous mineral acids being added or the reaction mixture beingintroduced into water or aqueous mineral acids. To achieve the bestyields, the pH of the product to be isolated is set here, i.e. usually aslightly acidic pH and in the case of heterocycles also a slightlyalkaline pH. The reaction products are, for example, isolated byextraction and evaporation of the organic phases; as an alternative, thesolvents can also be distilled from the hydrolysis mixture and theproduct which then precipitates can be isolated by filtration.

The purities of the products from the process of the invention aregenerally high, but for special applications (pharmaceuticalintermediates) it may nevertheless be necessary to carry out a furtherpurification step, for example by recrystallization with addition ofsmall amounts of activated carbon. The yields of the reaction productsare in the range from 70 to 99%; typical yields are, in particular, from85 to 95%.

The process of the invention is illustrated by the following examples,without being restricted thereto:

EXAMPLE 1 Preparation of 2,6-dimethoxyphenylboronic acid from resorcinoldimethyl ether and chlorocyclohexane

A mixture of 20.88 g of chlorocyclohexane (0.176 mol) and 22.1 g ofresorcinol dimethyl ether (0.16 mol) is added dropwise to a suspensionof 2.35 g of lithium granules (0.34 mol) in 300 g of THF at −50° C.,with an addition time of 2 hours being selected. After a conversion ofthe chlorocyclohexane of >97% determined by GC (total of 9 h), 16.6 g oftrimethyl borate (0.16 mol) are added dropwise at the same temperatureover a period of 15 minutes. After stirring for another 30 minutes at−50° C., the reaction mixture is poured into 120 g of water, the pH isadjusted to 6.3 by means of 37% HCl, and THF and cyclohexane aredistilled off at 35° C. under reduced pressure. 25 ml ofmethylcyclohexane are added to the product suspension, the colorlessproduct is filtered off with suction and is washed once with 25 ml ofcold methylcyclohexane and once with 25 ml of cold water. After drying,26.5 g of 2,6-dimethoxyphenylboronic acid (0.146 mol, 91%, meltingpoint: 104–107° C.) are obtained in the form of colorless crystals, HPLCpurity >99% a/a.

EXAMPLE 2 Preparation of 5-formylfuran-2-boronic acid from furfuraldiethyl acetal and chlorocyclohexane

A mixture of 20.88 g of chlorocyclohexane (0.176 mol) and 27.2 g offurfural diethyl acetal (0.16 mol) is added dropwise to a suspension of2.35 g of lithium granules (0.34 mol) in 300 g of THF at −65° C., withan addition time of 2 hours being selected. After a conversion of thechlorocyclohexane of >97% determined by GC (total of 10 h), 18.3 g oftrimethyl borate (0.176 mol) are added dropwise at the same temperatureover a period of 30 minutes. After stirring for another 30 minutes at−65° C., the reaction mixture is poured into 120 g of water, the pH isadjusted to 6.3 by means of 37% HCl, and THF and cyclohexane aredistilled off at a maximum of 35° C. under reduced pressure. The pH issubsequently adjusted to 1.5, the mixture is stirred until all theproduct has precipitated and the product is filtered off. After washingwith a little cold water and a little cold acetone and drying, 17.2 g of5-formyl-2-furanboronic acid (0.123 mol, 77%) are obtained in the formof a fine beige powders, HPLC purity >99% a/a.

EXAMPLE 3 Preparation of the methyl ether of salicylic acid from anisoleand chlorocyclohexane

A mixture of 20.88 g of chlorocyclohexane (0.176 mol) and 17.3 g ofanisole (0.16 mol) is added dropwise to a suspension of 2.35 g oflithium granules (0.34 mol) in 300 g of THF at −50° C., with an additiontime of 2 hours being selected once again. After a conversion of thechlorocyclohexane of >97% determined by GC (total of 11 h) dry carbondioxide is passed in at the same temperature until the solution issaturated with CO₂. After stirring for another 30 minutes at −50° C.,the reaction mixture is poured into 100 g of water, the pH is adjustedto 3.4 by means of 37% HCl and the solvent is distilled off at a maximumof 55° C. under reduced pressure. The colorless product is filtered offwith suction and, after drying, the methyl ether of salicylic acid(yield: 79%) is obtained in the form of colorless crystals, HPLCpurity >99% a/a. A further amount of the methyl ether of salicylic acidcan be obtained by extraction of the mother liquor with dichloromethane,drying over sodium sulfate and evaporation, total yield: 93%.

EXAMPLE 4 Preparation of 2,6-difluoroacetophenone from1,3-difluorobenzene and acetic anhydride

A solution of tert-butyllithium in THF is firstly produced by reacting9.25 g of tert-butyl chloride with 1.4 g of lithium granules in 100 g ofTHF at −78° C. After a conversion of >97% (GC a/a) has been reached,1,3-difluorobenzene (11.4 g) is added and the mixture is stirred foranother 30 minutes at −78° C. and subsequently for 2 hours at −65° C.The resulting solution of 2,6-difluoro-1-lithiobenzene is added dropwiseto a solution of 22 g of acetic anhydride in 35 g of THF which has beencooled to −5° C. After the usual aqueous work-up,2,6-difluoroacetophenone is obtained in a yield of 92%.

EXAMPLE 5 Preparation of 2-(thienyl)ethanol from thiophene and1-chloroheptane

A mixture of 145 g of 1-chloroheptane (1.1 mol) and 84.0 g of thiophene(1.0 mol) is added dropwise to a suspension of 14.5 g of lithiumgranules (2.1 mol) in 500 g of THF at −50° C. over a period of 3 hours.After a conversion of the chloroheptane of >97% determined by means ofGC (total of 9 h), 48 g of ethylene oxide (1.1 mol) are passed in at thesame temperature. After stirring for another 30 minutes at −50° C., thereaction mixture is poured into 120 g of water, the pH is adjusted to5.9 by means of 37% HCl and the low boilers are distilled off at amaximum of 55° C. under reduced pressure. After extraction with 3×175 gof dichloromethane, drying over sodium sulfate, filtering off thedesiccant and evaporation to dryness, thienylethanol is obtained in ayield of 83%.

EXAMPLE 6 Preparation of benzoic acid from benzene and chlorocyclohexane(deprotonation of benzene)

A mixture of 0.2 mol of chlorocyclohexane and 0.2 mol of benzene isadded dropwise to a suspension of 0.4 mol of lithium granules, 0.21 molof potassium tert-butoxide and 35 mg of biphenyl in 300 g of THF at −72°C. After a conversion of the chlorocyclohexane of >97% determined bymeans of GC (total of 24 h), carbon dioxide is passed in untilsaturation is achieved. The work-up is carried out by a method analogousto that in example 3; benzoic acid is obtained in a yield of 79%.

1. A process for preparing aryllithium compounds of the formulae (IV)and (VI) comprising the steps of a. reacting at least one halogencompound (I) with lithium metal to form a lithium compound of theformula (II)

b. reacting the lithium compound of formula (II) with aromatic compoundsof the formulae (III) and/or (V) to deprotonate the aromatic compoundsof formulae (III) and/or (V) and form lithium aromatics of formulae (IV)and/or (VI), wherein the steps a) and b) are carried out as a one-potreaction,

where R is methyl, a primary, secondary or tertiary alkyl radical havingfrom 2 to 12 carbon atoms, alkyl substituted by a radical selected fromthe group consisting of phenyl, substituted phenyl, aryl, heteroaryl,alkoxy, dialkylamino, alkylthio and substituted or unsubstitutedcycloalkyl having from 3 to 8 carbon atoms, Hal=fluorine, chlorine,bromine or iodine, X₁₋₄ are, independently of one another, each carbonor two adjacent radicals X₁₋₄R₁₋₄ can together be O, or S; the radicalsR₁₋₄ and the radical Z are substituents selected from the groupconsisting of hydrogen, methyl, primary, secondary or tertiary, cyclicor acyclic alkyl radicals having from 2 to 12 carbon atoms, substitutedcyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino,arylamino, diarylamino, phenyl, substituted phenyl, alkylthio,diarylphosphino, dialkyiphosphino, dialkylaminocarbonyl ordiarylaminocarbonyl, monoalkylaminocarbonyl or monoarylaminocarbonyl,CO₂ ⁻, hydroxyalkyl, alkoxyalkyl, fluorine and chlorine, CN andheteroaryl or two adyacent radicals R₁₋₄ form an aromatic or aliphaticring.
 2. The process as claimed in claim 1, wherein the process iscarried out at temperatures in the range from −100 to +25° C.
 3. Theprocess as claimed in claim 1, wherein the amount of lithium to be addedper mole of halogen to be reacted is in the range from 1.95 to 2.5 mol.4. The process as claimed claim 1, wherein the process is carried out inan ether solvent.
 5. The process as claimed in claim 1, said processfurther comprising adding organic redox systems to the reaction of theLi metal in step a).
 6. The process as claimed in claim 1, wherein thecompounds of the formula (III) or (V) include an alkoxy, F, Cl,substituted amino, CN, heteroaryl, aminoalkyl or hydroxyalkyl radical inthe ortho position relative to the deprotonating hydrogen.
 7. Theprocess as claimed in claim 1, further comprising the step of reactingthe compounds of the formulae (IV) and/or (VI) with an electrophile. 8.The process as claimed in claim 7, wherein the reaction with theelectrophile is carried out either after production of the lithiatedcompound (IV) and/or (V) or in a one-pot process by simultaneousaddition to the reaction mixture.
 9. The process as claimed in claim 7,wherein the electrophile is selected from the group consisting ofcarbon, boron or silicon compounds.
 10. The process as claimed in claim1, wherein two adjacent radicals R₁₋₄ form an aromatic or aliphaticring.
 11. A process as claimed in claim 1, wherein the lithium compoundof the formula (II) is present in a concentration ranging from 5 to 30%by weight.
 12. A process for preparing aryllithium compounds of theformula (IV) and (VI) comprising the steps of a. reacting at least onehalogen compound (I) with lithium metal to form a lithium compound ofthe formula (II)

b. reacting the lithium compound of formula (II) with aromatic compoundsof the formula (III) and/or (V) to deprotonate the aromatic compounds offormula (III) and/or (V) and form lithium aromatics of formula (IV)and/or (VI).

where R is methyl, a primary, secondary or tertiary alkyl radical havingfrom 2 to 12 carbon atoms, alkyl substituted by a radical selected fromthe group consisting of phenyl, substituted phenyl, aryl, heteroaryl,alkoxy, dialkylamino, alkylthio and substituted or unsubstitutedcycloakyl having from 3 to 8 carbon atoms, Hal=fluorine, chlorine,bromine or iodine, X₁₋₄ are, independently of one another, each carbonor two adjacent radicals X₁₋₄R₁₋₄ can together be O, or S; the radicalsR₁₋₄ and the radical Z are substituents selected from the groupconsisting of hydrogen, methyl, primary, secondary or tertiary, cyclicor acyclic alkyl radicals having from 2 to 12 carbon atoms, substitutedcyclic or acyclic alkyl groups, alkoxy, dialkylamino, alkylamino,arylamino, diarylamino, phenyl, substituted phenyl, alkylthio,diarylphosphino, dialkylphosphino, dialkylaminocarbonyl ordiarylaminocarbonyl, monoalkylaminocarbonyl or monoarylaminocarbonyl,CO₂ ⁻, hydroxyalkyl, alkoxyalkyl, fluorine and chlorine, CN andheteroaryl, or two adjacent radicals R₁₋₄ form an aromatic or aliphaticring, wherein (I) the process is carried out at temperatures in therange from −100 to −25° C. and (II) the process is carried out in anether solvent.